Long-Acting Semi-Solid Lipid Formulations

ABSTRACT

What is described is a semi-solid controlled release composition comprising a semi-solid lipid pharmaceutical active agent in a solution or a homogenous suspension, methods of using the composition for treating a disease, and methods of manufacturing the composition.

CROSS REFERENCE TO RELATED APPLICATIONS

This application claims benefit under 35 U.S.C. §119(e) of ProvisionalU.S. patent application No. 62/050,598, filed Sep. 15, 2014, the contentof which is incorporated herein by reference in its entirety.

TECHNICAL FIELD

The semi-solid formulations described herein relate to a semi-solidlipid matrix as a delivery vehicle, and controlled release semi-solidformulations comprising the semi-solid lipid vehicle andpharmaceutically active agents. The semi-solid formulations can be inthe form of an injectable or a topical formulation for controlleddelivery of pharmaceutical active agents, which are useful in thetreatment of various types of illness and disease.

BACKGROUND

Pharmaceutical active agents can be administered orally or as aninjectable. However, conventional oral and injectable formulations aretypically short-acting and often require frequent dosing to maintain atherapeutically effective concentration in the blood stream or at siteswhere treatment is needed. During the past three decades, controlleddrug delivery technologies have been developed to control the rate andperiod of drug delivery and target specific areas of the body fortreatment. Controlled drug delivery technologies offer a number ofadvantages such as prolonged and improved efficacy, decreased dosingfrequency, reduced peak-valley plasma concentration fluctuations,decreased side effects, site-specific delivery, ease of administration,patient compliance, and cost reduction. Although oral drug delivery isthe most frequently used route of drug administration, parenteral drugdelivery is a preferred route for rapid action. Drug products areadministered by implantation, or by subcutaneous, intramuscular, orintraperitoneal injection.

Sustained release or controlled release pharmaceutical drug productshave also been developed, e.g., by microencapsulation such asmicrospheres, microparticles, or implants. A drug delivery vehicle mostoften consists of a polymeric matrix from which drug is released bydiffusion from the matrix and/or by degradation of the matrix.

The earliest drug delivery systems (for the delivery of therapeuticagents) were based on a synthetic biodegradable polymer, polylactic acid(Yolles et al., Polymer News, 1:9-15 (1970)). Numerous other polymershave been described for use in biodegradable/bioerodible matrices forcontrolled release of active agents. U.S. Pat. Nos. 4,079,038,4,093,709, 4,131,648, 4,138,344, 4,180,646, 4,304,767 and 4,946,931describe various types of biodegradable/bioerodible polymers for thecontrolled delivery of active agents. Although many of these polymersare in the form of semi-solid, however, these semi-solid polymers areoften very sticky, and thus the formulations prepared cannot be easilyinjected.

While the above systems are useful, their manufacture processes arecomplicated, cumbersome and expensive. In addition, they are oftenassociated with an initial higher release of drug immediately afterinjection followed by inconsistent drug release kinetics, thus lack ofreliability in therapeutic effects in animal studies and human trials.

SUMMARY

One aspect of the description herein is a pharmaceutical composition,comprising a semi-solid gel consisting of one or more glycerides havinga structure selected from formulas I, II, III, IV, V, or VI

-   -   in which R′, R″, and R′″ are alkyl chains independently        consisting of a saturated natural fatty acid comprising 8 to 22        carbon atoms, a naturally occurring unsaturated fatty acids        comprising 16 to 22 carbons, a non-toxic organic dicarboxylic        acid comprising 6 to 10 carbon atoms, or a naturally occurring        omega saturated or unsaturated hydroxy acid, in which n is 1 to        10; in which the mixture of glycerides comprise at least two        different alkyl chains, and in which the mixture of glycerides        is at a concentration of 40 to 99 wt % of the pharmaceutical        composition;    -   an active ingredient at a concentration of 0.01 to 60 wt % of        the semi-solid gel, in which a dose of the pharmaceutical        composition comprises an amount of the active ingredient        effective to treat a subject in need thereof, in which the        active ingredient is fully solubilized or homogenously dispersed        in the semi-solid gel;    -   a first excipient consisting of one or more glycerides having a        structure selected from formulas I, II, III, IV, or V, in which        the first excipient is fully miscible in the semi-solid gel and        modifies release kinetics of the active ingredient from the        semi-solid gel so that the desired controlled release kinetics        and duration of several days to 4 months of the active        ingredient from the pharmaceutical composition was achieved when        measured in vitro at 37° C.; and    -   a second excipient consisting of one or more glycerides having a        structure selected from formulas I, II, III, IV, or V, in which        the second excipient is fully miscible with the semi-solid gel,        in which the second excipient modifies the viscosity of the        pharmaceutical composition to 20 to 2000 cPs at 30° C.;        in which the pharmaceutical composition consists of a        homogeneous, single phase semi-solid dosage form or a homogenous        semi-solid suspension dosage form suitable for injection into        the subject.

In one embodiment of the pharmaceutical composition, the activeingredient is a unit dose of an anti-inflammatory agent, an ophthalmicdrug, an antipsychotic, a 5-HT3 antagonist, or a glaucoma drug, foradministration to a site in a subject in a pharmaceutically effectiveamount. The active ingredient preferably is a compound selected frommeloxicam, loteprednol, risperidone, granisetron, or latanoprost, or afatty acid complex thereof.

In another embodiment of the pharmaceutical composition, the semi-solidgel comprises polyglyceryl-2-diisostearate, SOFTISAN® 378, SOFTISAN®645, or SOFTISAN® 701.

In another embodiment of the pharmaceutical composition, the firstexcipient comprises SOFTISAN® 701, SOFTISAN® 378, GELUCIRE®39/01,SUPPOCIRE® A, or SOFTISAN® 138, and adjusts the rate of release of theactive ingredient from the pharmaceutical composition. The firstexcipient may have a lower or higher HLB (hydrophobicity) than thesemi-solid gel. The first excipient preferably is at a concentration of0 to 30 wt % of the pharmaceutical composition

In another embodiment of the pharmaceutical composition, the secondexcipient comprises SOFTISAN® 701, SOFTISAN® 378, GELUCIRE® 39/01,SUPPOCIRE® A, or SOFTISAN® 138, and functions to decrease the viscosityof the pharmaceutical composition. The second excipient preferably is ata concentration of 0 to 30 wt % of the pharmaceutical composition.

In another embodiment of the pharmaceutical composition, the activeagent is a unit dose of an anti-inflammatory agent, an ophthalmic drug,an antipsychotics, a 5-HT₃ antagonist, or a glaucoma drug foradministration to a site in a subject in an amount effective to achievetheir therapeutic efficacy at the site or systemically. The active agentpreferably is at a concentration of 0.01 to 60 wt %, and more preferablyat a concentration of 3 to 40 wt %. The active agent is selected fromthe drugs consisting of meloxicam, loteprednol, risperidone,granisetron, or latanoprost, or a fatty acid complex thereof.

Another embodiment of the description herein, is a method for preventingor treating a disease or disorder comprising administering to a subjectin need thereof the pharmaceutical composition. The pharmaceuticalcomposition may consist of an injectable or a topical semi-solidformulation, which is administered by injection by a 21 gauge to 27gauge needle. Administration may be by subcutaneous, intramuscular,intraperitoneal injection, or by injection at the site of surgery.Administration can also be by topical application to skin or a mucousmembrane.

Another aspect of the description herein is method of manufacturing thepharmaceutical composition, comprising selecting an active agent in adosage amount sufficient to effectively treat a patient; fullysolubilizing or homogeneously mixing the active agent in a semi-solidgel consisting of one or more glycerides having a structure selectedfrom formulas I, II, III, IV, V, or VI

-   -   in which R′, R″, and R′″ are alkyl chains independently        consisting of a saturated natural fatty acid comprising 8 to 22        carbon atoms, a naturally occurring unsaturated fatty acids        comprising 16 to 22 carbons, a non-toxic organic dicarboxylic        acid comprising 6 to 10 carbon atoms, or a naturally occurring        omega saturated or unsaturated hydroxy acid, in which n is 1 to        10; in which the mixture of glycerides comprise at least two        different alkyl chains, in which the concentration of the active        agent is 0.01 to 60 wt % of the semi-solid gel;    -   measuring the release kinetics of the active agent from the        semi-solid gel resulting from step ii to determine if the        desired controlled release kinetics and duration of several days        to 4 months of the active ingredient from the semi-solid gel was        achieved when measured in vitro at 37° C.;    -   adding a first excipient to the semi-solid gel resulting from        step ii, in which the first excipient consists of one or more        glycerides having a structure selected from formulas I, II, III,        IV, or V, having a comparable HLB number than the semi-solid        gel, in which the first excipient is fully miscible in the        semi-solid gel and at a concentration sufficient to slow the        release of the active agent from the semi-solid gel to achieve        the desired controlled release kinetics and duration of several        days to 4 months is at a concentration of 0 to 30 wt % of the        pharmaceutical composition;    -   measuring the viscosity of the semi-solid gel containing the        active ingredient resulting from step iv to determine if the        viscosity is less than 2000 cPs at 30° C.; and adding a second        excipient to the semi-solid gel resulting from step iv, in which        the second excipient consists of one or more glycerides having a        structure selected from formulas I, II, III, IV, or V, in which        the second excipient is fully miscible with the semi-solid gel,        in which the second excipient modifies the viscosity of the        pharmaceutical composition to 20 to 2000 cPs at 30° C.;        in which the resulting pharmaceutical composition consists of a        homogeneous, single phase semi-solid dosage form or a homogenous        semi-solid suspension dosage form.

In one embodiment of the method of manufacturing the pharmaceuticalcomposition, the desired controlled release kinetics and duration(several days to 4 months) of the active ingredient from thepharmaceutical composition was achieved when measured in vitro at 37°C., further comprising selecting a free base or a salt form of theactive ingredient to slow its release rate from the semi-solid gel

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows granisetron release from different semi-solid compositionscontaining a main semisolid lipid carrier and a modifying excipient:semisolid 001 Gran: [S701/Sup A (75/25)]/granisetron (96/4); semisolid001 Gran PA: [S701/Sup A (75/25)]/granisetron PA (93/7); semisolid 001Gran OA: [S701/Sup A (75/25)]/granisetron OA (93/7); semisolid 002 Gran:[PGDS/Sup A (70/30)]/granisetron (96/4); and semisolid 003 Gran:[S645/Sup A (80/20)]/granisetron (96/4), all in 25 mM phosphate bufferedsaline, pH 7.4, 37° C.

FIG. 2A shows loteprednol etabonate release from different semi-solidcompositions containing one main semisolid lipid carrier with onemodifying excipient: semisolid 001 Lote: [S701/Sup A(75/25)]/loteprednol (97/3); semisolid 002 Lote: [PGDS/Sup A(70/30)]/loteprednol (97/3); and semisolid 003 Lote: [S645/Sup A(80/20)]/loteprednol (97/3), all in 25 mM phosphate buffered saline, pH7.4, 37° C.

FIG. 2B shows loteprednol etabonate and loteprednol etabonate fatty acidcomplex release from semi-solid compositions containing main semisolidlipid carrier with one modifying excipient: semisolid 001 Lote:[S701/Sup A (75/25)]/loteprednol (97/3); semisolid 001 Lote PA:[S701/Sup A (75/25)]/loteprednol PA (96/4); and semisolid 001 Lote OA:[S701/Sup A (75/25)]/loteprednol OA (96/4), all in 25 mM phosphatebuffered saline, pH 7.4, 37° C.

FIG. 3 shows meloxicam release from different semi-solid compositionscontaining one main semisolid lipid carrier with an without a modifyingexcipient: semisolid 001 Melo: [S701/Sup A (75/25)]/meloxicam (91/9);semisolid 002 Melo: [S378 (100)]/meloxicam (91/9); semisolid 003 Melo:[PGDS/Sup A (70/30)]/meloxicam (91/9); and semisolid 004 Melo: [S645/SupA (80/20)]/meloxicam (91/9), all in 25 mM phosphate buffered saline, pH7.4, 37° C.

FIG. 4 shows risperidone release from a semi-solid compositioncontaining a main semisolid lipid carrier and a modifying excipient:semisolid 001 Risp PA: [S701/Sup A (90/10)]/risperidone PA (90/10), in25 mM phosphate buffered saline, pH 7.4, 37° C.

FIG. 5A shows latanoprost release from different semi-solid compositionscontaining one main semisolid lipid carrier with one modifyingexcipient: semisolid 001 Lata: [S701/Sup A (90/10)]/latanoprost (95/5);semisolid 002 Lata: [S378 (100)]/latanoprost (95/5); semisolid 003 Lata:[PGDS/Sup A (70/30)]/latanoprost (95/5); and semisolid 004 Lata:[S645/Sup A (80/20)]/latanoprost (95/5), all in 25 mM phosphate bufferedsaline, pH 7.4, 37° C.

FIG. 5B shows latanoprost release from different semi-solidcompositions: semisolid 001 Lata: [S701/Sup A (90/10)]/latanoprost(95/5), in 25 mM phosphate buffered saline, pH 7.4, 37° C.

DETAILED DESCRIPTION OF ILLUSTRATIVE EMBODIMENTS

Advantages of Bioerodible Semisolid Depot Technology

Biocompatible and Bioerodible Semi-Solid Lipid Depot Containing ActiveDrugs

The semi-solid formulations described herein provide a prolonged periodof drug release such that therapeutic concentrations of the drug areachieved rapidly and maintained for several days up to four months. Thepotential benefit of the prolonged release profile is to achieve rapiddrug action, maintaining higher levels of active drug at the site wheretreatment is needed over time to potentially provide greater therapeuticeffect.

One of the benefits of bioerodible, semisolid depot technology is thatno significant initial burst is found in the formulations describedherein. Typically, controlled release injections are associated with aninitial burst (higher release of drug immediately after injection). Invitro drug release and animal studies have shown that injectablecomposition based on the bioerodible semisolid depot technologydescribed herein produce less post-injection burst that is typicallyassociated with other commercially available injectable controlledrelease technologies. For example, NUTROPIN® (somatropin of rDNA originfor injection) has a drug release profile of huge burst followed by veryslow drug release.

Drug concentration in the semisolid depot technology described hereincan be considerably greater than what is typical with other controlledrelease technologies. For example, a long-acting mepivacaine has beendeveloped using this semi-solid drug delivery technology in which onlyabout 3 wt % of mepivacaine can to be loaded into the polyorthoestervehicle due to the drug's low solubility in the vehicle.

The semisolid depot formulations exhibit described herein have very lowviscosity, about 10,000 mPa·s or less at 30° C., preferably 1000 mPa·sor less. Therefore, they can be injected through a small needle such as23 gauge or even 25 gauge needles, and will exhibit minimal pain(similar to aqueous solution injection) during injection. Additionally,since the semisolid formulations described herein have a higher capacityfor drug loading, less volume of drug product is required to beinjected. Small injection volumes and low viscosity semi-solidformulations result in easier and less painful administration.Polyorthoester semi-solid formulations have a viscosity of thousands ofmPa·s at 30° C., which is difficult to be injected with a 21 gaugeneedle.

The formulations described herein comprise semisolid lipids that areglycerides of glycerol with natural fatty acids. These compounds arereadily hydrolyzed to glycerol and free fatty acids by lipase. Thesecompounds are non-toxic, and exhibit excellent biocompatibility in thebody. The formulations described herein are biodegradable, bioerodible,and fully resorbable. In animal studies, at two weeks after dosing, noadverse effect of the semi-solid formulation on wound healing wasobserved. The administration site appeared to be pinkish, and the ratsciatic nerve appeared to be normal, no inflammation, necrosis,ulceration, or infection was observed.

Compared to microspheres and other polymer-based controlled releaseinjectable systems, the semisolid formulations described herein arereadily manufactured at low cost. The active ingredient(s) andsemi-solid vehicle components are simply mixed at without the use ofsolvents at relatively low elevated temperatures. Note that sincesemi-solid lipid and low-melting point lipid (less than 50° C., and mostpreferably less than 40° C.) (modifying excipient) are used, themanufacturing process may be at about 60° C.

Further, the formulations described herein can be administered directlyfor site specific delivery. Since the formulations provide a sustaineddrug release over a period of days to months resulting in increasedduration of pharmacological action, and reduced frequency of drugadministration. The formulations also produce reduced side effects (dueto local drug delivery) when compared with systemic administration. Theease of use should produce improved patient compliance.

All technical and scientific terms are used herein according to theirconventional definitions as they are commonly used and understood bythose of ordinary skill in the art of drug delivery. Specific terms forthe description herein will be defined below.

DEFINITIONS

The term “semi-solid” denotes the physical state of a material that isflowable under a moderate pressure. More specifically, the semi-solidmaterial has a viscosity of less than 10,000 cps (mPa·s) at 30° C. Oneof the excipient components can have a viscosity of about 5,000 to 6,000mPa·s. After mixing with a viscosity reducer and active ingredient, theoverall viscosity will be reduced to hundreds of cps for the finalformulation/drug product.

The term “thixotropic” means a shear thinning property of a fluid or gelmaterial when mixed or agitated. Certain gels or fluids that are thick(viscous) under static conditions will flow (become thin, less viscous)over time when shaken, agitated, or otherwise stressed. They then take afixed time to return to a more viscous state. Many gels and colloids arethixotropic materials, exhibiting a stable form at rest but becomingfluid when agitated. Thixotropy is the tendency for the viscosity of aliquid to decrease when subjected to shear. Thixotropic Index is theratio of two viscometer readings. The higher the difference in the tworeadings, the more thixotropic the material is, and easier to move. Theterm “thixotropic” is used in its conventional sense to refer to a gelcomposition that can liquefy or at least exhibit a decrease in apparentviscosity upon application of mechanical force such as shear force. Theextent of the reduction is in part a function of the shear rate of thegel when subjected to the shearing force. When the shearing force isremoved, the viscosity of the thixotropic gel returns to a viscosity ator near that prior to being subjected to the shearing force.Accordingly, a thixotropic gel may be subjected to a shearing force wheninjected from a syringe which temporarily reduces its viscosity duringthe injection process. When the injection process is completed, theshearing force is removed and the gel returns very near to its previousstate.

A “thixotropic agent” as used herein is one that increases thethixotropy of the composition in which it is contained, promoting shearthinning and enabling use of reduced injection force.

The term “bioerodible” refers to a material that gradually decomposes,dissolves, hydrolyzes and/or erodes in situ. Generally, the“bioerodible” semi-solid lipids described herein are materials that arehydrolizable, and bioerode in situ primarily through both lipolysis andhydrolysis.

The semi-solid lipids, solvent and other agents of the description mustbe “biocompatible”; that is they must not cause irritation or necrosisin the environment of use. The environment of use is a fluid environmentand may comprise a subcutaneous, subconjunctival, intramuscular,intravascular (high/low flow), intramyocardial, adventitial,intratumoral, or intracerebral portion, wound sites, tight joint spacesor body cavity of a human or animal.

Low-Solubility Semi-Solid Lipids of the Formulation

The semi-solid lipids useful in the formulation described herein are amixture of one or more monoglycerides, diglycerides, or triglycerides oflow water solubility having the structure of I, II, III, IV, V, or lowhydrophilic-lipophilic balance (HLB) polyglyceryl esters with thestructure of VI

in which R′, R″, and R′″ are independent fatty acid moiety or hydrogen,and n is 1-10. The fatty acids include saturated natural fatty acidscontaining 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21 or 22carbon atoms, preferably 8-18 carbon atoms, such as caprylic acid,capric acid, lauric acid, myristic acid, palmitic acid, stearic acid,arachidic acid, or behenic acid; or naturally occurring mono-unsaturatedfatty acids such as palmitoleic acid, cis-vaccenic acid, or oleic acid;or polyunsaturated fatty acids such as linoleic acid, α-linolenic acid,arachidonic acid, eicosapentaenoic acid, and docosahexaenoic acid;naturally occurring omega saturated and unsaturated hydroxy acids suchas 16-hydroxy palmitic acid, 18-hydroxy stearic acid,2-hydroxy-docosanoic, 15-hydroxy-hexadecanoic acid,17-hydroxy-octadecanoic acid, 2-hydroxy-oleic acid, 2-hydroxy-linoleicacid, or ricinoleic acid; additional naturally occurring fatty acidssuch as vernolic acid or furanoid fatty acids; and finally non-toxicorganic dicarboxylic acid containing 6, 7, 8, 9, or 10 carbon atoms suchas adipic acid, azelaic acid, or sebacic acid which can be used alongwith other fatty acids. A small portion of these acids can be added tothe fatty acid mixtures and react with glycerol to produce the mixedesters.

In addition, polyglyceryl esters with an HLB value of less than 4 andmolecular weight of less than 2,000 Dalton, such aspolyglyceryl-2-diisostearate (HLB=3.8), polyglyceryl-10-decaoleate(HLB=3.5), or polyglyceryl ester of mixed vegetable fatty acids(HLB=2.5), are also useful semi-solid vehicle.

Triglycerides are typically manufactured through direct esterificationof glycerol with defined fatty acid blends and have therefore precisecomposition and properties regarding melting point, polarity (hydroxylvalue), and consistency. Partial glycerides are esters of glycerol withfatty acids, whereby only a part of the existing hydroxyl groups areesterified. Some hydroxyl groups within the glycerol ester are freecontributing to the polar properties of the material.

The semi-solid lipids compositions in the present description comprisetriglycerides, diglycerides, and monoglycerides of mixed esters in arelatively viscous liquid or paste form with an aqueous solubility ofless than 0.1 mg/mL, with an HLB value of not more than 6, preferablyless than 5. Glycerides of short-chain fatty acid with aliphatic chainsof fewer than six carbons (i.e., butyric acid) and glycerides ofmedium-chain fatty acids with aliphatic chains of 6, 7, 8, 9, 10, 11 or12 carbons are typically in the form of mobile liquid and are difficultto form a long-lasting depot in the human body at the body temperatureof 37° C. and physiologic pH. Triglycerides of long-chain fatty acidswith aliphatic chains 13, 14, 15, 16, 17, 18, 19, 20 or 21 carbons, andvery long chain fatty acids with aliphatic chains longer than 22 carbonstypically have a higher melting point and are more likely to be a hardwaxy solid at room temperature. As the number of fatty acid carbonsincreases, the solubility of the formed triglycerides decreases in thehuman body. Therefore, the triglycerides of mixed esters and partialglycerides of fatty acids useful for the formulation described hereinare mixed esters containing medium chain fatty acids. Myristictriglyceride, palmitic triglyceride, and stearic triglyceride are in theform of solid powder or flakes with a melting point of 57° C., 63° C.and/or 71° C., respectively. Fatty acids with aliphatic chains of 6, 7,8, 9, 10, 11 or 12 carbons, which have high polarity and thereforeexhibit superior solvent characteristics for active drugs, and longchain fatty acids with aliphatic chains of 13 to 21 carbons which tendsto increase melting point and hardness, so a proper mixed esterscontaining both medium-chain and long-chain fatty acids can be in thephysical form of a soft paste.

Commercial mixtures of glycerides are readily available. For example,SOFTISAN® 378 (S378) is a mixture of caprylic/capric/myristic/stearictriglycerides, containing all four types of fatty acids, is an off-whiteto yellowish soft paste with a drop point of 39° to 42° C., and thismaterial is practically insoluble in water at 20° C. (with a watersolubility of less than 0.1 mg/mL). At 40° C., after this material beingmelted and become a liquid, it has a dynamic viscosity of 30 mPa·s. Forthis type of glycerides of saturated fatty acids, the medium-chain fattyacids play the role of solubilizing the active ingredient into thesemi-solid lipid, while the hydrophobicity/lipophilicity of long-chainfatty acids is a main factor controlling drug release, control the slowerosion/dissolution of semi-solid lipid, and the release of the activeingredient.

Viscosity also plays a role in controlling the release of activeingredients from the semi-solid depot. Other fatty acids such as omegasaturated such as hydroxystearic acid (and unsaturated hydroxy acids)which tends to increase viscosity of the material and other non-toxicorganic dicarboxylic acid to increase polarity of the material andsolubility of the active drugs. These functional groups such as hydroxylgroups (—OH) and carboxylic groups (—COOH), can form intra andintermolecular hydrogen bonding, and can increase the viscosity of theglycerides of saturated fatty acids. They can also form molecularinteractions with drug molecules, and contribute to retain the activeingredient inside the semi-solid depot. For example,caprylic/capric/isostearic/hydroxyl-stearic/adipic glycerides is a mixedester of a relatively viscous yellowish liquid with a viscosity ofapproximately 6000 mPa·s at 20° C., and this material is practicallyinsoluble in water (with a water solubility of less than 0.1 mg/mL).Introducing hydroxyl-steric fatty acid with hydroxyl groups and adipicdicarboxylic acid with carboxylic groups changes this mixed ester into ahigh viscosity liquid. When additional hydrophobic stearic acid isintroduced, the resulting material(caprylic/capric/isostearic/hydroxylstearic/stearic acid/adipicglycerides) becomes a sticky paste with a viscosity of about 540 mPa·sat 50° C.

Unsaturated glycerides with naturally occurring omega unsaturatedhydroxy acids, and monounsaturated and polyunsaturated fatty acidstypically have a lower melting point and are more likely to be liquid orsoft paste. Some hydroxyl groups within the glycerol ester are freecontributing to the polar properties of the material, and potential goodsolubility of active ingredients. Especially, glycerides of unsaturatedhydroxy acids show even better solubility for low solubility activeingredients due to the presence of hydroxyl groups. For example,ricinoleic acid partial glycerides is a white to yellowish paste with aviscosity of approximately 500-600 mPa·s at 30° C., and this material isdispersible in water. Other unsaturated partial glyceride examples areglyceryl oleate, glyceryl linoleate, glyceryl linoleate, glycerylhydroxyoleate, glyceryl hydroxylinoleate, and glyceryl monooleatelinoleate, and glyceryl monooleate. Since these materials containunsaturated components, interaction with oxygen must be considered.Antioxidant(s) may be added to the material to increase stability.

Polyglyceryl esters are formed chemically by esterification of fattyacids, largely saturated or mono-unsaturated, to one or several hydroxylgroups of polyglycerol with the structural formula, VI:

In which the value of n is not more than 10, preferably less than 4, andR′, R″, and R′″ each may be a fatty acid moiety or hydrogen.

Only 30% to 50% of the total amount of hydroxyl groups typically isesterified by fatty acids. Normally, they are used as emulsifying agentsdue to their amphiphilic characteristics. Almost all the commerciallyavailable polyglyceryl esters are relatively hydrophilic, with a highHLB value of greater than 4, and are either soluble in water ordispersible in water. They are used as water additives and products, andare not hydrophobic enough to be used as a controlled semi-soliddelivery vehicle.

However, polyglyceryl esters such as polyglyceryl-2-diisostearate(HLB=3.8), polyglyceryl-10-decaoleate (HLB=3.5), polyglyceryl ester ofmixed vegetable fatty acids (HLB=2.5), bis-diglyceryl polyacyladipate,diglycerin laurate, diglycerin myristate, diglycerin oleate, andpolyglyceryl ricinoleate with an HLB value of not more than 4,preferably less than 3, can be used as a semi-solid vehicle component.They can be used as oil additives due to their lowhydrophilic-lipophilic balance value, and are fully compatible withsemi-solid lipid vehicle components. They typically exist as a viscousliquid due to the presence of multiple hydroxyl groups, and will becomea soft paste when a solid lipid was added as a modifying excipient. Themolecular weight of the polyglyceryl esters should be less than 2,000Dalton, preferably less than 1,500 Dalton, and more preferably not morethan 1,000 Dalton. For example, polyglyceryl-2-diisostearate (HLB=3.8)is slightly yellow viscous liquid, when a waxy solid lipid G39/01 (aglyceride of C₁₂ to C₁₈ fatty acids) is added, the mixture becomes asoft paste. Polyglyceryl-10-decaoleate (HLB=3.5) is a viscous liquid,when a waxy solid lipid G39/01 (a glyceride of C₁₂ to C₁₈ fatty acids)is added, the mixture becomes a soft paste.

The useful semi-solid lipids (low HLB triglycerides of mixed esters,partial glycerides (including monoglycerides and diglycerides) of fattyacids, and low HLB polyglyceryl esters) should be hydrophobic enough,and have low solubility with an aqueous solubility of less than 1 mg/mLin physiological pH buffer at 37° C., preferably less than 0.1 mg/mL.They are in the form of either a soft paste, or a viscous liquid at roomtemperature.

The useful main semi-solid lipids alone, the main semi-solid lipid mixedwith the modifying excipients (the final delivery vehicle), and thedelivery vehicle with the active ingredients can form a definedlong-lasting depot once administered into the body at 37° C., and willgradually degrade/erode, and be dissolved into the body liquids, and thesemi-solid lipids will eventually be hydrolyzed to natural free glyceroland free fatty acids by lipase through a process called lipolysis.

Modifying Excipients

The modifying excipients suitable for the present description arepharmaceutically acceptable and semi-solid lipid compatible materials.These materials can be in the form of liquid, semi-solid, or solid atroom temperature, and are fully compatible with the semi-solid lipid toform a single phase semi-solid delivery vehicle for active drugs.

More specifically, suitable modifying excipients can be alsotriglycerides of mixed esters and partial glycerides of fatty acids asdescribed in the main semi-solid lipid vehicle. Since these modifyingexcipients are structurally similar to the main semi-solid lipidvehicle, they are expected to be fully compatible. Physically, thesematerials can be in the form of liquid, semi-solid, or solid at roomtemperature, and should also have low solubility with an aqueoussolubility of less than 1 mg/mL in physiological pH buffer at 37° C.,preferably less than 0.1 mg/mL with an HLB value of not more than 6,preferably less than 5. The modifying excipient is preferably to havecomparable solubility as the main semi-solid lipid. If the modifyingexcipient is too hydrophilic and water soluble, it will cause asignificant burst of the active drug(s), especially when the activedrugs are relatively soluble, which may cause undesirable side effects.If the modifying excipient is significantly more insoluble than the mainsemi-solid lipid, it will retain in the body significantly longer whenthe active drug and the main semi-solid lipid is completely dissolvedand resorbed by the body.

The purposes of adding modifying excipients to the main semi-solid lipidvehicle is to modify the release kinetics of the active drugs from thedelivery vehicle, to reduce the viscosity of the main lipid vehicle, tomodify the texture or consistency of the vehicle, and to ensure thefinal drug product/formulation remain as a long-lasting well-defineddepot to control the gradual release of active drugs. Any one of thethree types of the useful semi-solid lipids, triglycerides of mixedesters, partial glycerides of fatty acids, and low HLB polyglycerylesters, can be used as a modifying excipient, which will be a mixture oftwo semi-solid lipids. Another type of useful modifying excipient is asolid triglyceride, diglyceride or monoglyceride with a melting point ofless than 60° C., preferably around and slightly above body temperature(35° to 50° C.). When the melting point gets too high, it will cause thehardening of the semisolid vehicle during storage, and this solidtriglyceride or partial glycerides could retain the body significantlylonger. For example, solid triglycerides and partial glycerides with amelting point of around and slightly above body temperature aretypically in the form of waxy solid, and can serve as a lubricant (dueto the waxy property from the long alkyl chains of fatty acids) thatreduces the viscosity of the relatively viscous liquid or paste. Forexample, a 10 to 20 wt % of a triglycerides of C₁₀ to C₁₈ fatty acids(S138), hydrogenated cocoglycerides (a different percentage mixture ofC₁₀ to C₁₈ fatty acids with melting points from 25° to 50° C.), glyceryllaurate, glyceryl myristate, glyceryl palmitate, glyceryl monostearate(HLB=5), glyceryl hydroxyl stearate, or a glyceride of C₁₂ to C₁₈ fattyacids (G39/01, HLB=1) with a melting point of 37° to 40° C., a glycerideof C₁₀ to C₁₈ fatty acids (SUPPOCIRE® A, HLB=1) with a melting point of35° to 36.5° C., glyceryl cocoate (glyceryl monococoate, dicocoate ortricococoate), hydrogenated palm/palm kernel oils (a mixture ofmonoglycerides, diglycerides and triglycerides with different percentageof C₁₀, C₁₂, C₁₄, C₁₆ or C₁₈ fatty acids with melting points from 20° to45° C.), can be added to the relatively viscous yellowish liquid ofcaprylic/capric/isostearic/hydroxylstearic/adipic glycerides (a mixedester), and changed the delivery vehicle to a relatively non-viscoussoft paste. This could not only make the semi-solid depot a more definedshape in the body, and potentially prolong the drug release duration,but also improve the ability of the semi-solid formulation to beadministered by syringe.

The concentrations of modifying excipient in the delivery vehicle mayvary. For example, the concentration of the excipient in the vehicle maybe in the range of about 1 to 50 wt %, preferably about 5 to 30 wt %,and more preferably about 10 to 20 wt %.

The delivery vehicle of the semi-solid lipid formulation comprises onemain semi-solid lipid, and typically one and potentially more modifyingexcipients selected from those described in the preceding section. Thedelivery vehicle can be prepared by mixing or blending together the mainsemi-solid lipid and the modifying excipients homogenously. The mixingand blending can be performed by any methods or using any suitabledevices to achieve a smooth homogeneous and non-sticky semi-solidmixture at an elevated temperature without the use of any solvents, orwith the help of organic solvents to dissolve the active agents orvehicle components.

Pharmaceutical Semi-Solid Formulations

“Active agent” includes any locally or systemically acting active agentswhich may be administered to a subject by topical application or bysubcutaneous, subconjunctival, intradermal, intramuscular, intraocular,or intra-articular injection. Examples of these agents include, but notlimited to, anti-infectives (including antibiotics, antivirals,fungicides such as itraconazole, scabicides or pediculicides),antiseptics (e.g., benzalkonium chloride, chlorhexidine gluconate,nitrofurazone, or nitromersol), steroids (e.g., estrogens, progestins,androgens, or adrenocorticoids), therapeutic polypeptides (e.g.,exenatide, octreotide, insulin, erythropoietin, or morphogenic proteinssuch as bone morphogenic protein), corticosteroids, analgesics andanti-inflammatory agents (NSAIDs) (e.g., aspirin, ibuprofen, naproxen,ketorolac, indomethacin, meloxicam, COX-1 inhibitors, or COX-2inhibitors), chemotherapeutic and anti-neoplastic agents (e.g.,paclitaxel, mechlorethamine, cyclophosphamide, fluorouracil,thioguanine, carmustine, lomustine, melphalan, chlorambucil,streptozocin, methotrexate, vincristine, bleomycin, vinblastine,vindesine, dactinomycin, daunorubicin, doxorubicin, or tamoxifen),5-hydroxytryptophan (serotonin) 3 (5-HT₃) receptor antagonists for theprevention and treatment of nausea and vomiting following chemotherapy(e.g., granisetron, ondansetron, or palonosetron), narcotics (e.g.,morphine, meperidine, or codeine), antipsychotics including typicalantipsychotics (e.g., haloperidol or fluphenazine) and atypicalantipsychotics (e.g., risperidone, clozapine, olanzapine, orpaliperidone), antiangiogenic agents (e.g., combrestatin,contortrostatin, or anti-vascular endothelial growth factor),polysaccharides, vaccines, antigens, DNA and other polynucleotides,antisense oligonucleotides, or siRNA.

The present semi-solid formulation described herein may also be appliedto other locally acting active agents, such as astringents,antiperspirants, irritants, rubefacients, vesicants, sclerosing agents,caustics, escharotics, keratolytic agents, sunscreens and a variety ofdermatologics including hypopigmenting and antipruritic agents.

Exemplary compositions of this semi-solid formulation described herein,and their uses, include:

(1) compositions containing local anesthetics, in combination withanti-inflammatory agents, antibiotics, or corticosteroids, for theprolonged local pain and inflammation relief, and for the prevention ortreatment of infection (inhibition of microorganism growth).

(2) compositions containing 5-HT₃ receptor antagonists such asgranisetron, ondansetron, palonosetron, and the like, for the prolongedprevention and treatment of nausea and vomiting following chemotherapy.

(3) compositions containing ophthalmic drugs, corticosteroid such asloteprednol for the treatment of inflammation of the eye; glaucoma drugsuch as brimonidine for the treatment of open-angle glaucoma or ocularhypertension; antiangiogenic agents such as combrestatin for thetreatment of macular degeneration and retinal angiogenesis; and othercompositions for the controlled release of ophthalmic drugs to the eye.

(4) compositions containing anti-inflammatory agents such as the NSAIDs,e.g., meloxicam, ibuprofen, naproxen, or COX-1 or COX-2 inhibitors, orglucocorticosteroids, for intra-articular injection.

(5) compositions containing antipsychotics including atypicalantipsychotics such as risperidone, clozapine, olanzapine, paliperidone,and the like, and typical antipsychotics for the prolonged treatment ofschizophrenia, schizoaffective disorder, the mixed and manic states ofbipolar disorder, and irritability in autistic people.

The active agents may be present as the free base, or as an acidaddition salt, or as a mixture thereof. A mixture of two differentagents or a mixture of the same active agent in two forms, the free baseform and the acid addition salt, may be used to achieve the desiredpharmacological effect and release rate and duration.

The active agents (free base) can be readily converted into a salt withfatty acids and other pharmaceutically acceptable acids. Both saturatedand unsaturated fatty acids such as lauric acid, myristic acid, palmiticacid, and oleic acid are natural fatty acids, and can be used. Othernon-toxic organic acids such as pamoic acid can also be used. Thisconversion can increase its compatibility and solubility in thesemi-solid vehicle. The selected active agents can be converted into asalt in advance before being incorporated into the semi-solid vehicle,or can be added into the semi-solid vehicle simultaneously at a 1:1molar ratio or other molar ratios during the formulation manufacturingprocess.

The semi-solid injectable form of an active agent of the semi-solidformulation described herein may be prepared by mixing with the deliveryvehicle already formed or directly mixed together with the mainsemi-solid lipid and the modifying excipients. The active agents may befirst milled into fine particles before mixing with the otheringredients. The mechanical mixing process is performed at a suitabletemperature to completely melt the semi-solid lipid and modifyingexcipients into a solution, and dissolve or mill by any mechanical meansthe active drugs into the delivery vehicle to from a clear solution or ahomogeneous suspension, or use organic solvents to dissolve the activeagent and the vehicle components. A vacuum may be applied to avoid airbubbles, and nitrogen may be applied to reduce oxidation of active drugsand the delivery vehicle components. After achieving a homogeneous anduniform pharmaceutical composition, the active agent semi-solidformulation can be cooled down to ambient temperature.

The amount of active agent(s) present in the composition can vary over awide range depending on the a number of factors, such as thetherapeutically effective dose of the active drug, the desired durationof biological or therapeutic effect, and the release profile of thecomposition. The concentration of the active agent may be in the rangeof about 0.01 to 60 wt %, preferably about 5 to 40 wt %, or morepreferably about 10 to 40 wt %.

The concentration of the main semi-solid lipid may be in the range ofabout 1 to 99 wt %, preferably about 5 to 80 wt %. The concentration ofthe first modifying excipient may be in the range of about 1 to 50 wt %,preferably about 5 to 20 wt %. The concentrations of the second type ofmodifying excipients may be in the range of about 0.1 to 10 wt %,preferably about 0.5 to 5 wt %. In addition, other pharmaceuticallyacceptable agents such as antioxidants, preservatives, and other inertagents such as coloring or flavoring agents may be added.

This pharmaceutical semi-solid composition of the present semi-solidformulation described herein has a smooth non-tacky semi-solid paste.Therefore, the composition can be filled into syringes with a 21 gaugeto 25 gauge needle for subcutaneous, subconjunctival, intradermal,intramuscular, epidural or intrathecal injection, or can also beconveniently applied onto already-open sites such as surgicalwounds/site or exposed skin or mucous membrane.

After administration by injection or topical application, the activeagent is release from the composition in a sustained and controlledmanner. The rate of release may be regulated in a variety ways toaccommodate the desired duration of therapeutic effect. For example, therate may be increased or decreased by using different level of lowsolubility semi-solid lipid and different level of low solubility saltsof the active agents with acids. It may also be altered by selectingdifferent modifying excipients or by changing their amount, or thecombination thereof. In addition, lower water solubility forms of activeagents such as their base forms, or as complexes with fatty acids may beused to delay the release of active agents.

EXAMPLES Example 1 Granisetron

Granisetron(1-methyl-N-((1R,3r,5S)-9-methyl-9-azabicyclo[3.3.1]nonan-3-yl)-1H-indazole-3-carboxamide)(KYTRIL®) is a serotonin 5-HT₃ receptor antagonist used as an antiemeticto treat nausea and vomiting following chemotherapy. Its main effect isto reduce the activity of the vagus nerve, which is a nerve thatactivates the vomiting center in the medulla oblongata. It does not havemuch effect on vomiting due to motion sickness. It does not have anyeffect on dopamine receptors or muscarinic receptors.

The solubility of active ingredients in the main single semi-solid lipidas a vehicle was determined, and potential suitable main singlesemi-solid lipids for the active ingredient were identified.

The solubility study was performed as follows. The targeted amount ofactive ingredient and the semi-solid lipid vehicle was weighed andtransferred to a glass vial and sealed. The mixture was heated to about90° C. in a water bath for about three minutes, and then vortexed forone minute. The procedure was repeated five times to completely dissolveall components and form a clear solution.

For solubility results, if the active ingredient is completely dissolvedin the vehicle, the result is “completely soluble”; if there is minimalamount active ingredient particle left not dissolved, then the result is“almost completely soluble”; if part of the active ingredient iscompletely dissolved, then the result is “partially soluble” with anvisual rough estimate of percentage of active ingredient dissolved(e.g., <50%, ˜50%, or >50%); if only minimal amount active ingredient isdissolved or not soluble at all, then the result is “slightly soluble”or “insoluble”.

The semi-solid formulations were cooled to ambient temperature. Theyappeared as a semi-transparent or opaque soft paste. Crystallization orprecipitation of active ingredients was checked.

The solubility results were summarized in Table 1, which shows that thethree single semi-solid lipid, 5701, PGDS, and 5645 can solubilize thetargeted amount of granisetron (21 mg) in 0.5 gram of the vehicle.

TABLE 1 Solubility results for granisetron in single semi-solid lipidvehicle Semi-solid API Lipid Vehicle Amount Sample ID Vehicle Amount (g)(mg) Solubility Results Granisetron F1 S701 0.5 g 21 mg Completelysoluble Granisetron F2 S378 0.5 g 21 mg Partially soluble (~80%)Granisetron F3 PGDS 0.5 g 21 mg Almost completely soluble Granisetron F4S645 0.5 g 21 mg Almost completely soluble

The following formulations comprising granisetron were prepared.

-   -   Semisolid 001 Gran: [S701/Sup A (75/25)]/granisetron (96/4) or        (96 wt %/4 wt %)    -   Semisolid 001 Gran PA: [S701/Sup A (75/25)]/granisetron PA        (93/7)    -   Semisolid 001 Gran OA: [S701/Sup A (75/25)]/granisetron OA        (93/7)    -   Semisolid 002 Gran: [PGDS/Sup A (70/30)]/granisetron (96/4)    -   Semisolid 003 Gran: [S645/Sup A (80/20)]/granisetron (96/4)

The semi-solid formulations were prepared by weighing the vehiclecomponents and the drug into a glass vial, and closing the lid. S645consists of caprylic/capric/isosteric/hydroxyl-steric/adipic glycerides,mixed esters; PGDS is polyglyceryl-2-diisostearate; 5701 consists ofricinoleic acid partial glycerides; and Sup A consists of glycerides ofC₁₂ to C₁₈ fatty acids. The vehicle components were melted by heating to90° C. in a water bath, and granisetron was dissolved to form a clearsolution and became a semi-transparent soft paste after cooling down toroom temperature.

The solubility results for granisetron in semi-solid lipid formulationsare shown in Table 2. Table 2 shows that all of the 4 semi-solid lipidvehicles (semi-solid lipid+modifying excipient) can solubilize thetargeted amount of 25 mg granisetron or granisetron PA or OA in 0.5 gramof the vehicle.

TABLE 2 Solubility results for granisetron in semi-solid vehicle(semi-solid lipid + modifying excipient) Semi-solid Targeted SolubilitySample ID Vehicle (Granisetron/Vehicle) Solubility Results Semisolid 001S701:Sup A 21 mg/0.5 g Completely Gran (75:25) soluble Semisolid 001S701:Sup A (21 mg Gran + 17 mg Completely Gran PA (75:25) PA)/0.5 gsoluble Semisolid 001 S701:Sup A (21 mg Gran + 19 mg Completely Gran OA(75:25) OA)/0.5 g soluble Semisolid 002 PGDS:Sup 21 mg/0.5 g Almost GranA (70:30) completely soluble Semisolid 003 S645:Sup A 21 mg/0.5 g AlmostGran (80:20) completely soluble

For in vitro release determination, about 50 mg of the semi-solidformulation was weighed and enclosed in a porous semi-permeablemembrane, and then placed into glass bottles with screw caps. 100 mL of50 mM phosphate saline buffer (PBS), pH 7.4 was added to each bottle.The test bottles were transferred to a 37° C. oven without agitation. Atvarious time points, bottles were removed and samples of about 1 mL wereremoved and analyzed for granisetron by light absorption at 206 nm. 50mL of the buffer in each test bottle was removed and replaced with 51 mLof fresh buffer so that the PBS buffer in each bottle was maintained at100 mL. The drug release profiles of the listed semi-solid formulationsare summarized in the FIG. 1.

FIG. 1 showed granisetron and granisetron fatty acid complex releasefrom three different semi-solid compositions containing main semisolidlipid carrier with one modifying excipient. Semisolid 001 Gran,semisolid 002 Gran, and semisolid 003 Gran all contain approximately 4wt % granisetron, and yielded similar granisetron release profile forabout one week with about 20 to 30% drug released at 6 hour time point.Semisolid 001 Gran PA and semisolid 001 Gran OA both contain about thesame 4 wt % granisetron excluding fatty acid, and approximately 7 wt %granisetron combined with palmitic acid or oleic acid, and yielded aslower, and better controlled release profile with about 16% and 14%drug released respectively after 6 hours.

Example 2 Loteprednol Etabonate

Loteprednol (chloromethyl17-ethoxycarbonyloxy-11-hydroxy-10,13-dimethyl-3-oxo-7,8,9,11,12,14,15,16-octahydro-6H-cyclopenta[a]phenanthrene-17-carboxylate)(ALREX® or LOTEMAX®) in the form of the ester loteprednol etabonate is acorticosteroid used in ophthalmology. Ocular applications for this druginclude the treatment of inflammation of the eye due to allergies(according to the prescription information sheet), as well as chronicforms of keratitis (e.g., adenoviral or Thygeson's keratitis), vernalkeratoconjunctivitis, pingueculitis, and episcleritis. The drug haslittle or no effect on intraocular pressure.

The solubility of loteprednol was measured and scored as described inExample 1. Table 3 shows that the 3 single semi-solid lipid, 5701, PGDS,and 5645 can solubilize the targeted amount of loteprednol etabonate (14mg) in 0.5 gram of the vehicle.

TABLE 3 Solubility results for loteprednol etabonate in singlesemi-solid lipid vehicle Semi-solid API Lipid Vehicle Amount Sample IDVehicle Amount (g) (mg) Solubility Results Loteprednol F1 S701 0.5 g 14mg Completely soluble Loteprednol F2 S378 0.5 g 14 mg Partially soluble(~50%) Loteprednol F3 PGDS 0.5 g 14 mg Almost completely solubleLoteprednol F4 S645 0.5 g 14 mg Almost completely soluble

The following formulations comprising loteprednol etabonate wereprepared.

-   -   Semisolid 001 Lote: [S701/Sup A (75/25)]/loteprednol (97/3)    -   Semisolid 001 Lote PA: [S701/Sup A (75/25)]/loteprednol PA        (96/4)    -   Semisolid 001 Lote OA: [S701/Sup A (75/25)]/loteprednol OA        (96/4)    -   Semisolid 002 Lote: [PGDS/Sup A (70/30)]/loteprednol (97/3)    -   Semisolid 003 Lote: [S645/Sup A (80/20)]/loteprednol (97/3)

The solubility results for loteprednol in semi-solid lipid formulationsare shown in Table 4. Table 4 shows that all of the 4 semi-solid lipidvehicles (semi-solid lipid+modifying excipient) can solubilize thetargeted amount of 14 mg loteprednol or granisetron PA or OA in 0.5 gramof the vehicle.

TABLE 4 Solubility results for loteprednol in semi-solid vehicle(semi-solid lipid + modifying excipient) Targeted Solubility Semi-solid(Loteprednol/ Sample ID Vehicle Vehicle) Solubility Results Semisolid001 S701:Sup A 14 mg/0.5 g Completely soluble Lote (75:25) Semisolid 001S701:Sup A (14 mg Lote + 8 mg Completely soluble Lote PA (75:25) PA)/0.5g Semisolid 001 S701:Sup A (14 mg Lote + 9 mg Completely soluble Lote OA(75:25) OA)/0.5 g Semisolid 002 PGDS:Sup A 14 mg/0.5 g Almost completelyLote (70:30) soluble Semisolid 003 S645:Sup A 14 mg/0.5 g Almostcompletely Lote (80:20) soluble

The semi-solid formulations were prepared by weighing the vehiclecomponents and the drug into a glass vial, and closing the lid. S645consists of caprylic/capric/isosteric/hydroxyl-steric/adipic glycerides,mixed esters; PGDS is polyglyceryl-2-diisostearate; S701 consists ofricinoleic acid partial glycerides; and Sup A consists of glycerides ofC₁₂ to C₁₈ fatty acids. The vehicle components were melted by heating to90° C. in a water bath, and loteprednol was dissolved to form a clearsolution and became a semi-transparent soft paste after cooling down toroom temperature.

For in vitro release determination, about 50 mg of each semi-solidformulation was weighed and enclosed in a porous semi-permeablemembrane, and then placed into glass bottles with screw caps. 100 mL of50 mM PBS, pH 7.4, was added to each bottle. The test bottles weretransferred to a 37° C. oven without agitation. At various time points,bottles were removed and samples of about 1 mL were removed and analyzedfor loteprednol etabonate by light absorption at 277 nm. 50 mL of thebuffer in each test bottle was removed and replaced with 51 mL of freshbuffer so that the PBS buffer in each bottle was maintained at 100 mL.

The drug release profiles of all the listed semi-solid formulations aresummarized in the FIGS. 2A and 2B.

FIG. 2A showed loteprednol etabonate release from three differentsemi-solid compositions containing main semisolid lipid carrier with onemodifying excipient. Semisolid 001 Lote, semisolid 002 Lote, andsemisolid 003 Lote all contain approximately 3 wt % loteprednoletabonate, and yielded similar loteprednol etabonate release profile forabout one week with about 14 to 24% drug released after 6 hours.

FIG. 2B showed loteprednol etabonate and loteprednol etabonate fattyacid complex release from the same semi-solid composition containingmain semisolid lipid carrier with one modifying excipient. Semisolid 001Lote, semisolid 001 Lote PA and semisolid 001 Lote OA all containapproximately 3 wt % loteprednol etabonate excluding fatty acid. Forsemisolid 001 Lote, about 14% loteprednol etabonate was released at 6hour time point, while only 5% and 1% of loteprednol etabonate werereleased for semisolid 001 Lote PA and semisolid 001 Lote OA,respectively, after 6 hours.

Example 3 Meloxicam

Meloxicam(4-hydroxy-2-methyl-N-(5-methyl-2-thiazolyl)-2H-1,2-benzothiazine-3-carboxamide-1,1-dioxide)(MOBIC®) is a nonsteroidal anti-inflammatory drug (NSAID) with analgesicand fever reducer effects. It is a derivative of oxicam, closely relatedto piroxicam, and falls in the enolic acid group of nonsteroidalanti-inflammatory drugs (NSAIDs). Meloxicam starts to relieve pain about30-60 minutes after administration.

The solubility of meloxicam was measured and scored as described inExample 1. Table 5 shows that none of the 4 single semi-solid lipid,5701, PGDS, 5378 and 5645 can solubilize the targeted amount ofmeloxicam (50 mg) in 0.5 gram of the vehicle. Therefore, it is notpossible to prepare a semi-solid “solution” formulation for that doselevel; however, it is still possible to prepare a homogeneous meloxicamsemi-solid suspension formulation.

TABLE 5 Solubility results for meloxicam in single semi-solid lipidvehicle Semi-solid Vehicle API Lipid Amount Amount Sample ID Vehicle (g)(mg) Solubility Results Meloxicam F1 S701 0.5 g 50 mg Partially soluble(<30%), formed nice semi-solid suspension Meloxicam F2 S378 0.5 g 50 mgPartially soluble (<30%), formed nice semi-solid suspension Meloxicam F3PGDS 0.5 g 50 mg Partially soluble (<30%), formed nice semi-solidsuspension Meloxicam F4 S645 0.5 g 50 mg Partially soluble (<30%),formed nice semi-solid suspension

The following formulations of meloxicam were prepared.

-   -   Semisolid 001 Melo: [S701/Sup A (75/25)]/meloxicam (91/9)    -   Semisolid 002 Melo: [S378 (100)]/meloxicam (91/9)    -   Semisolid 003 Melo: [PGDS/Sup A (70/30)]/meloxicam (91/9)    -   Semisolid 004 Melo: [S645/Sup A (80/20)]/meloxicam (91/9)

The solubility results for meloxicam in semi-solid lipid formulationsare shown in Table 6. Table 6 shows that none of the four semi-solidlipid vehicles (semi-solid lipid+modifying excipient) can solubilize thefull targeted amount of meloxicam 50 mg in 0.5 gram of the vehicle.Therefore, meloxicam was prepared as homogeneous meloxicam semi-solidsuspension formulations.

TABLE 6 Solubility results for meloxicam in semi-solid vehicle(semi-solid lipid + modifying excipient) Targeted Solubility Semi-solid(Meloxicam/ Solubility Sample ID Vehicle Vehicle) Results Semisolid 001Melo S701:Sup A 50 mg/0.5 g Nice semi-solid (75:25) suspension Semisolid002 Melo S378 (100) 50 mg/0.5 g Nice semi-solid suspension Semisolid 003Melo PGDS:Sup A 50 mg/0.5 g Nice semi-solid (70:30) suspension Semisolid004 Melo S645:Sup A 50 mg/0.5 g Nice semi-solid (80:20) suspension

The semi-solid formulations were prepared by weighing the vehiclecomponents and the drug into a glass vial, and closing the lid. S378 arecaprylic/capric/myristic/steric triglycerides; S645 arecaprylic/capric/isosteric/hydroxyl-steric/adipic glycerides, mixedesters; PGDS are polyglyceryl-2-diisostearate; S701 are ricinoleic acidpartial glycerides; and Sup A are glycerides of C₁₂ to C₁₈ fatty acids.

After heating to 90° C. in a water bath, both vehicle components werecompletely melted, and meloxicam was partially dissolved to form ayellowish solution with micronized meloxicam drug particles suspended.Upon cooling to room temperature, the cap was opened and excess moisturearound the vial was wiped, and a stainless steel spatula was used to mixthoroughly to form a nice homogeneous soft paste suspension formulation.

For in vitro release determination, about 50 mg of each semi-solidformulation was weighed and enclosed in a porous semi-permeablemembrane, and then placed into glass bottles with screw caps. 100 mL of50 mM PBS, pH 7.4, was added to each bottle. The test bottles weretransferred to a 37° C. oven without agitation. At various time points,bottles were removed and samples of about 1 mL were removed and analyzedfor meloxicam by light absorption at 362 nm. 50 mL of the buffer in eachtest bottle was removed and replaced with 51 mL of fresh buffer so thatthe PBS buffer in each bottle was maintained at 100 mL.

The drug release profiles of all the listed semi-solid formulations aresummarized in the FIG. 3.

FIG. 3 showed meloxicam release from four different semi-solidsuspension formulation compositions containing main semisolid lipidcarrier with one modifying excipient. Semisolid 001 Melo, semisolid 002Melo, semisolid 003 Melo, and semisolid 004 Melo all containapproximately 9 wt % meloxicam, and yielded different meloxicam releaseprofile raging from about two weeks to more than four months. As theoverall hydrophobicity of the formulation depots increased, their watersolubility decreased, and thus resulted in slower dissolution rate andlonger drug release duration.

Example 4 Risperidone

Risperidone(4-[2-[4-(6-fluorobenzo[d]isoxazol-3-yl)-1-piperidyl]ethyl]-3-methyl-2,6-diazabicyclo[4.4.0]deca-1,3-dien-5-one(RISPERDAL®, RISPERDAL CONSTA®, RISPERDAL M-TAB®, RISPERDAL QUICKLETS®)is an antipsychotic drug mainly used to treat schizophrenia (includingadolescent schizophrenia), schizoaffective disorder, the mixed and manicstates of bipolar disorder, and irritability in people with autism.

The solubility of risperidone was measured and scored as described inExample 1. Table 7 shows that none of the 4 single semi-solid lipid,5701, PGDS, 5378 and 5645 can solubilize the targeted amount ofrisperidone (25 mg) in 0.5 gram of the vehicle. Therefore, it is notpossible to prepare a semi-solid “solution” formulation for that doselevel with this hot-melt method.

TABLE 7 Solubility results for risperidone in single semi-solid lipidvehicle Semi-solid Vehicle API Lipid Amount Amount Sample ID Vehicle (g)(mg) Solubility Results Risperidone F1 S701 0.5 g 25 mg Partiallysoluble (~30%) Risperidone F2 S378 0.5 g 25 mg Partially soluble (~30%)Risperidone F3 PGDS 0.5 g 25 mg Partially soluble (~30%) Risperidone F4S645 0.5 g 25 mg Partially soluble (~30%)

A formulation of risperidone was prepared as follows: Semisolid 001 RispPA: [S701/Sup A (90/10)]/risperidone PA (90/10).

This formulation was prepared by solvent evaporation method. Bothvehicle components and risperidone were weighed and transferred into aglass vial. S701 consists of ricinoleic acid partial glycerides; and SupA consists of glycerides of C₁₂ to C₁₈ fatty acids. About 3 mL acetonewas added, and the vial was sealed and vortexed for about 5 minutesuntil risperidone was dissolved. The vial was opened, and placed in ahood for 4 hours to remove the solvent, then heated at about 50° C.(slightly yellowish clear solution) under vacuum for about 8 hours toremove the solvent. The drug risperidone partially precipitated outafter cooling down to room temperature, and this risperidone semi-solidformulation became a nice smooth homogeneous soft paste suspensionformulation.

The solubility results for risperidone in semi-solid lipid formulationsare shown in Table 8. Table 8 shows that none of the 4 semi-solid lipidvehicles (semi-solid lipid+modifying excipient) can solubilize the fulltargeted amount of meloxicam 50 mg in 0.5 gram of the vehicle.Therefore, risperidone was prepared as very smooth semi-solid suspensionformulations by solvent-evaporation method.

TABLE 8 Solubility results for risperidone in semi-solid vehicle(semi-solid lipid + modifying excipient) Semi-solid Targeted SolubilitySolubility Sample ID Vehicle (Risperidone/Vehicle) Results Semisolid 001S701:Sup A (25 mg Risp + 23 mg Completely Risp PA (90:10) PA)/0.5 gsoluble Semisolid 002 Risp S378 (100) 25 mg/0.5 g Partially soluble(~30%) Semisolid 003 Risp PGDS:Sup A 25 mg/0.5 g Partially (70:30)soluble (~30%) Semisolid 004 Risp S645:Sup A 25 mg/0.5 g Partially(80:20) soluble (~30%)

For in vitro release determination, about 50 mg of the semi-solidformulation was weighed and enclosed in a porous semi-permeablemembrane, and then placed into a glass bottle with a screw cap. 100 mLof 50 mM PBS, pH 7.4, was added to the bottle. The test bottle wastransferred to a 37° C. oven without agitation. At various time points,bottle was removed and samples of about 1 mL were removed and analyzedfor risperidone by light absorption at 246 nm. 50 mL of the buffer inthe test bottle was removed and replaced with 51 mL of fresh buffer sothat the PBS buffer in each bottle was maintained at 100 mL.

The drug release profiles of the semi-solid formulations are summarizedin the FIG. 4.

FIG. 4 showed risperidone release from one semi-solid compositioncontaining main semisolid lipid carrier with one modifying excipient.Semisolid 001 Risp PA contains approximately 10 wt % risperidonecombining with palmitic acid, and yielded a linear (zero-order releasekinetics) drug release profile for more than five weeks.

Example 5 Latanoprost

Latanoprost (XALATAN®) is used for treating glaucoma or ocularhypertension by reducing intraocular pressure.

The solubility of latanoprost was measured and scored as described inExample 1. Table 9 shows that all of the four single semi-solid lipids,S701, PGDS, S378 and S645 can solubilize the targeted amount oflatanoprost 25 mg in 0.5 gram of the vehicle.

TABLE 9 Solubility results for latanoprost in single semi-solid lipidvehicle Semi-solid Vehicle Lipid Amount API Amount Sample ID Vehicle(mg) (mg) Solubility Results Latanoprost F1 S701 500 mg   25 mgCompletely soluble Latanoprost F2 S378 250 mg 12.5 mg Completely solubleLatanoprost F3 PGDS 250 mg 12.5 mg Completely soluble Latanoprost F4S645 250 mg 12.5 mg Completely soluble

The following formulations of latanoprost were prepared as in Example 1.

-   -   Semisolid 001 Lata: [S701/Sup A (90/10)]/latanoprost (95/5) or        (95 wt %/5 wt %)    -   Semisolid 002 Lata: [S378 (100)]/latanoprost (95/5)    -   Semisolid 003 Lata: [PGDS/Sup A (70/30)]/latanoprost (95/5)    -   Semisolid 004 Lata: [S645/Sup A (80/20)]/latanoprost (95/5)

The solubility results for latanoprost in semi-solid lipid formulationsare shown in Table 10. Table 10 shows that all of the 4 semi-solid lipidvehicles (semi-solid lipid plus modifying excipient) can solubilize thetargeted amount of 25 mg latanoprost in 0.5 gram of the vehicle.

TABLE 10 Solubility results for latanoprost in semi-solid vehicle(semi-solid lipid plus modifying excipient) Targeted SolubilitySemi-solid (Latanoprost/ Sample ID Vehicle Vehicle) Solubility ResultsSemisolid 001 S701:Sup A 25 mg/0.5 g Completely soluble Lata (90:10)Semisolid 002 S378 (100) 25 mg/0.5 g Completely soluble Lata Semisolid003 PGDS:Sup A 25 mg/0.5 g Completely soluble Lata (70:30) Semisolid 004S645:Sup A 25 mg/0.5 g Completely soluble Lata (80:20)

FIG. 5A showed latanoprost release from four different semi-solidcompositions containing one main semisolid lipid carrier with onemodifying excipient. Semisolid composition from semisolid 001 Lata tosemisolid 004 Lata containing approximately 5 wt % latanoprost showed agood controlled release from about a month to three months. All foursemisolid compositions employed one major semi-solid lipid with amodifying lipid. As the overall hydrophobicity of the formulation depotsincrease, their water solubility decrease, and thus resulting slowerdissolution rate and longer drug release duration. Semisolid 001 Lataand semisolid 003 Lata yielded about very linear three month and onemonth drug release; while semisolid 003 Lata and semisolid 004 Latayielded about one month drug release, then followed by very slowrelease.

FIG. 5B showed latanoprost release from three different amounts (50,100, and 200 mg) of a semi-solid formulation, semisolid 001 Lata:[S701/Sup A (90/10)]/Latanoprost (95/5). As the amounts/volumes of theformulation increases, the release rate of latanoprost relative to thetotal drug loading decreased as it take longer time for the drug todiffuse out and the vehicle to erode, and thus the total drug releaseduration is also longer.

Example 4 Viscosity

The viscosity of the semi-solid formulations were determined on acalibrated Brookfield RVDV-I Prime CP model viscometer using conespindle CPE-51. The semi-solid formulation samples stored in sealedglass vials were first heated to about 40° to 50° C. in an oven untilthe samples became a flowable viscous liquid. Then approximately 0.3gram of each sample was weighed into the center the warmed sample cup.Bubbles were avoided when possible. The sample cup was attached to theviscometer, and the viscosity was measured at an appropriate speed ofrotation so that the % torque is between 10% and 100%. The viscosity and% torque at the target temperature were recorded. Due to the soft pastenature of these materials at room temperature, the viscosity ofsemi-solid formulations was determined at 30° C. at that point thesemi-solid formulations become a flowable viscous liquid/semi-solidunder pressure.

The viscosity values for the main semi-solid lipid are relatively low,typically below 1000 cPs at 30° C., except for S645, which is a veryviscous liquid. The viscosity values of the four main semi-solidcomponents were determined at 30° C. and summarized in Table 11.

TABLE 11 Viscosity values of the main semi-solid lipid Sample IDViscosity (cP) at 30° C. S378 neat 45 S701 neat 563 PGDS neat 427 S645neat 2454

The semi-solid drug delivery vehicle typically contains two or morecomponents, the main semi-solid component with one or two modifyingexcipients. The overall semi-solid vehicle typically exhibits even lowerviscosity, since the modifying excipient often acts as a waxy lubricant,thus further reducing the viscosity of semi-solid vehicle when comparedwith the main semi-solid component. The viscosity values for the fourmain components modified with 10 wt % to 30 wt % of Sup A weredetermined and summarized in Table 12.

TABLE 12 Viscosity values for the overall semi-solid vehicle (mainsemi-solid lipid + modifying excipient) Sample ID Viscosity (mPa · s) at30° C. S701:Sup A (75:25) 295 S701:Sup A (90:10) 427 PGDS:Sup A (70:30)191 S645:Sup A (80:20) 1028

For the first main semi-solid lipid S378, the viscosity was very lowviscosity at about 50 cPs before being modified with any modifyingexcipient. For the main semi-solid lipid S701, the viscosity of theoverall semi-solid vehicle reduced from 563 cPs (for neat S701) to 427cPs and 295 cPs respectively after being modified with 10 wt % and 25 wt% of Sup A. For the 3rd main semi-solid lipid PGDS, the viscosity of theoverall semi-solid vehicle reduced from 427 cPs (for neat PGDS) to 191cPs after being modified with 30 wt % of Sup A. For the 4th mainsemi-solid lipid S645, the viscosity of the overall semi-solid vehiclereduced from 2454 cPs (for neat S645) to 1028 cPs (58% reduction ofviscosity) after being modified with 20 wt % of Sup A.

The viscosity results for the semi-solid formulations listed in the invitro release study were summarized in Table 13. The viscosity value ofthese semi-solid formulations ranges from 55 cPs to 1168 cPs, with themajority of them below 500 cPs at 30° C. The overall semi-solidformulations exhibited very lower viscosity.

TABLE 13 Viscosity results for semi-solid formulations Viscosity (mPa ·s) Sample ID Semi-solid Formulation Composition at 30° C. Semisolid 001Gran [S701/Sup A (75/25)]/Granisetron (96/4) 378 Semisolid 001 Gran PA[S701/Sup A (75/25)]/Granisetron PA (93/7) 359 Semisolid 001 Gran OA[S701/Sup A (75/25)]/Granisetron OA (93/7) 349 Semisolid 002 Gran[PGDS/Sup A (70/30)]/Granisetron (96/4) 239 Semisolid 003 Gran [S645/SupA (80/20)]/Granisetron (96/4) 1162 Semisolid 001 Lote [S701/Sup A(75/25)]/Loteprednol (97/3) 326 Semisolid 001 Lote PA [S701/Sup A(75/25)]/Loteprednol PA (96/4) 323 Semisolid 001 Lote OA [S701/Sup A(75/25)]/Loteprednol OA (96/4) 310 Semisolid 002 Lote [PGDS/Sup A(70/30)]/Loteprednol (97/3) 220 Semisolid 003 Lote [S645/Sup A(80/20)]/Loteprednol (97/3) 1168 Semisolid 001 Risp PA [S701/Sup A(90/10)]/Risperidone PA (90/10) 437 Semisolid 001 Lata [S701/Sup A(90/10)]/Latanoprost (95/5) 458 Semisolid 002 Lata [S378]/Latanoprost(95/5) 55 Semisolid 003 Lata [PGDS/Sup A (70/30)]/Latanoprost (95/5) 205Semisolid 004 Lata [S645/Sup A (80/20)]/Latanoprost (95/5) 1058

Once the active ingredient, granisetron, loteprednol etabonate, orlatanoprost, was incorporated into the final semi-solid drug deliveryvehicle through a hot melt process the mixture formed a semi-solidsolution formulation with the active drug molecularly dispersed in thesemi-solid vehicle media. The active drugs only slightly increase theviscosity of the semi-solid formulations when compared with thesemi-solid vehicle. As the drug (solid powder) loading increases, thesoft semi-solid paste formulation can change to a relatively hardsemi-solid paste formulation, thus resulting in increased viscosity.

For the active ingredient risperidone, since this drug can't beincorporated into the semi-solid vehicle by the hot melt process, thesemi-solid formulation was prepared by solvent evaporation processinstead.

For the active ingredient meloxicam, since this drug can't beincorporated into the semi-solid vehicle by the hot melt process, or beincorporated by solvent evaporation process with a volatile solvent, sothe meloxicam semi-solid formulations were prepared as a homogenoussuspension semi-solid formulation using micronized meloxicam drug, andtheir viscosities were not determined. However, all four semi-solidsuspension formulations using S378, 5701, PGDS and 5645 as the mainsemi-solid lipid components are readily injectable with 21 gaugeneedles.

All the listed semi-solid formulations for in vitro release study usingS378, S701, and PGDS as the main semi-solid lipid with the viscosityranging from 55 cPs to 500 cPs at 30° C. are readily injectable with 23gauge needles, while the three semi-solid formulations using S645 as themain semi-solid lipid are readily injectable with 21 gauge needles(still injectable with a 23 gauge needle with some resistance).

What is claimed:
 1. A pharmaceutical composition, comprising i. asemi-solid gel consisting of one or more glycerides having a structureselected from formulas I, II, III, IV, V, or VI

wherein R′, R″, and R′″ are alkyl chains independently consisting of asaturated natural fatty acid comprising 8 to 22 carbon atoms, anaturally occurring unsaturated fatty acids comprising 16 to 22 carbons,a non-toxic organic dicarboxylic acid comprising 6 to 10 carbon atoms,or a naturally occurring omega saturated or unsaturated hydroxy acid,wherein n is 1 to 10; wherein the mixture of glycerides comprise atleast two different alkyl chains, and wherein the mixture of glyceridesis at a concentration of 40 to 99 wt % of the pharmaceuticalcomposition; ii. an active ingredient at a concentration of 0.01 to 60wt % of the semi-solid gel, wherein a dose of the pharmaceuticalcomposition comprises an amount of the active ingredient effective totreat a subject in need thereof, wherein the active ingredient is fullysolubilized or homogenously dispersed in the semi-solid gel; iii. afirst excipient consisting of one or more glycerides having a structureselected from formulas I, II, III, IV, or V, wherein the first excipientis fully miscible in the semi-solid gel and modifies release kinetics ofthe active ingredient from the semi-solid gel so that the desiredcontrolled release kinetics and duration of the active ingredient fromthe pharmaceutical composition was achieved when measured in vitro at37° C., wherein the duration of release is several days to four months;and iv. a second excipient consisting of one or more glycerides having astructure selected from formulas I, II, III, IV, or V, wherein thesecond excipient is fully miscible with the semi-solid gel, wherein thesecond excipient modifies the viscosity of the pharmaceuticalcomposition to 20 to 2000 cPs at 30° C.; wherein the pharmaceuticalcomposition consists of a homogeneous, single phase semi-solid dosageform or a homogenous semi-solid suspension dosage form suitable foradministration by injection into the subject.
 2. The pharmaceuticalcomposition of claim 1, wherein the active ingredient is atherapeutically effective amount of an anti-inflammatory agent, anophthalmic drug, an antipsychotics, a 5-HT3 antagonist, or an glaucomadrug.
 3. The pharmaceutical composition of claim 1, wherein the activeingredient is selected from meloxicam, loteprednol, risperidone,granisetron, or latanoprost, or a fatty acid complex thereof.
 4. Thepharmaceutical composition of claim 1, wherein the semi-solid gelcomprises polyglyceryl-2-diisostearate, SOFTISAN® 378, SOFTISAN® 645, orSOFTISAN®
 701. 5. The pharmaceutical composition of claim 1, wherein thefirst excipient comprises SOFTISAN® 701, SOFTISAN® 378, GELUCIRE® 39/01,SUPPOCIRE® A, or SOFTISAN®
 138. 6. The pharmaceutical composition ofclaim 1, wherein the first excipient adjusts the rate of release of theactive ingredient from the pharmaceutical composition.
 7. Thepharmaceutical composition of claim 6, wherein the first excipient has alower or higher HLB (hydrophobicity) than the semi-solid gel.
 8. Thepharmaceutical composition of claim 1, and wherein the first excipientis at a concentration of 0 to 30 wt % of the pharmaceutical composition.9. The pharmaceutical composition of claim 1, wherein the secondexcipient comprises SOFTISAN® 701, SOFTISAN® 378, GELUCIRE® 39/01,SUPPOCIRE® A, or SOFTISAN®
 138. 10. The pharmaceutical composition ofclaim 1, wherein the second excipient decreases the viscosity of thepharmaceutical composition.
 11. The pharmaceutical composition of claim1, wherein the second excipient is at a concentration of 0 to 30 wt % ofthe pharmaceutical composition.
 12. The pharmaceutical composition ofclaim 1 wherein the active agent is a unit dose of an anti-inflammatoryagent, an ophthalmic drug, an antipsychotics, or a 5-HT₃ antagonist foradministration to a site in a subject in an amount effective to achievetheir therapeutic efficacy at the site or systemically.
 13. Thepharmaceutical composition of claim 1 wherein the active agent is at aconcentration of 0.01 to 60 wt %.
 14. The pharmaceutical composition ofclaim 1 wherein the active agent is at a concentration of 3 to 40 wt %.15. The pharmaceutical composition of claim 1, wherein the active agentis selected from the drugs consisting of meloxicam, loteprednol,risperidone, granisetron, or latanoprost, or a fatty acid complexthereof.
 16. The pharmaceutical composition of claim 1, wherein thecomposition consists of an injectable or a topical semi-solidformulation.
 17. A method for preventing or treating a disease ordisorder comprising administering to a subject in need thereof thepharmaceutical composition of claim
 1. 18. The method of claim 17,wherein the pharmaceutical composition is administered by injection by a21 gauge to 27 gauge needle.
 19. The method of claim 17, wherein theadministration is by subcutaneous, intramuscular, intraperitonealinjection, or by injection at the site of surgery.
 20. The method ofclaim 17, wherein the administration is by topical application to skinor mucous membrane.
 21. A method of manufacturing a pharmaceuticalcomposition, comprising i. selecting an active agent in a dosage amountsufficient to effectively treat a patient; ii. fully solubilizing orhomogeneously mixing the active agent in a semi-solid gel consisting ofone or more glycerides having a structure selected from formulas I, II,III, IV, V, or VI

wherein R′, R″, and R′″ are alkyl chains independently consisting of asaturated natural fatty acid comprising 8 to 22 carbon atoms, anaturally occurring unsaturated fatty acids comprising 16 to 22 carbons,a non-toxic organic dicarboxylic acid comprising 6 to 10 carbon atoms,or a naturally occurring omega saturated or unsaturated hydroxy acid,wherein n is 1 to 10; wherein the mixture of glycerides comprise atleast two different alkyl chains, wherein the concentration of theactive agent is 0.01 to 60 wt % of the semi-solid gel; iii. measuringthe release kinetics of the active agent from the semi-solid gelresulting from step ii to determine if the desired controlled releasekinetics and duration of the active ingredient from the semi-solid gelwas achieved when measured in vitro at 37° C., wherein the duration ofrelease is several days to four months; iv. adding a first excipient tothe semi-solid gel resulting from step ii, wherein the first excipientconsists of one or more glycerides having a structure selected fromformulas I, II, III, IV, or V, having a comparable HLB number than thesemi-solid gel, wherein the first excipient is fully miscible in thesemi-solid gel and at a concentration sufficient to slow the release ofthe active agent from the semi-solid gel to achieve the desiredcontrolled release kinetics and duration is at a concentration of 0 to30 wt % of the pharmaceutical composition, wherein the duration ofrelease is several days to four months; v. measuring the viscosity ofthe semi-solid gel containing the active ingredient resulting from stepiv to determine if the viscosity is less than 2000 cPs at 30° C.; andvi. adding a second excipient to the semi-solid gel resulting from stepiv, wherein the second excipient consists of one or more glycerideshaving a structure selected from formulas I, II, III, IV, or V, whereinthe second excipient is fully miscible with the semi-solid gel, whereinthe second excipient modifies the viscosity of the pharmaceuticalcomposition to 20 to 2000 cPs at 30° C.; wherein the resultingpharmaceutical composition consists of a homogeneous, single phasesemi-solid dosage form or a homogenous semi-solid suspension dosageform.
 22. The method of claim 18, wherein the desired controlled releasekinetics and duration of the active ingredient from the pharmaceuticalcomposition was achieved when measured in vitro at 37° C., wherein theduration of release is several days to four months, further comprisingselecting a free base or a salt form of the active ingredient todecrease its release rate from the semi-solid gel.